Our aim is to determine the application of new PEs that specifically maintain microvascular and heart function, allowing the lowering of the transfusion trigger, which would minimize or delay the use of blood transfusions. Conventional plasma expanders (PEs) lower blood viscosity and their use beyond the transfusion trigger causes: 1) Arteriolar vasoconstriction and decreased blood flow;2) Reduced number of capillaries with red blood cell transit (i.e., functional capillary density, FCD);and, 3) Lowered blood pressure. These effects occur also in the microcirculation of the heart, causing heart function, and cardiac output to decrease. In normal conditions, shear stress on the endothelium generated by blood flow produces sufficient nitric oxide (NO) resulting in normal vascular tone and blood flow, restricting mitochondrial tissue oxygen consumption. Conversely, lowered blood viscosity and decreased heart function obtained with the presently used PEs do not generate the vessel wall shear stress necessary to produce sufficient NO for cardiovascular regulation when used beyond the transfusion trigger. We identified alginate, a high viscosity PE and polyethylene glycol conjugated albumin, a moderate viscosity PE, as fluids that restore FCD, heart function and mean arterial blood pressure in extreme hemodilution. We propose that these effects arise from improvement of heart function by maintaining microvascular perfusion of the myocardium and limiting damage to endothelial function and vessel wall integrity by interaction with the glycocalyx. Our research will test the hypothesis that there is a direct relationship between microvascular recovery and improvement of heart function in extreme hemodilution and shock resuscitation. Studies will use microvascular analysis by direct in vivo measurement of micro-pO2, micro-NO, capillary pressure, microvascular flow, FCD, tissue pH, reactive oxygen species (ROS) formation and cellular necrosis and apoptosis. These studies will be correlated with electrocardiographic measurements aimed at documenting myocardial ischemia. Heart function will also be assessed by measuring contractility (dP/dt) and cardiac output. Blood flow distribution to major organs will be measured using fluorescent tracers. Parallel studies will be made in isolated microvessels to determine the effects of the proposed materials on microvessel reactivity by interaction with the glycocalyx. Glycocalyx studies will also be made in the hamster window chamber model. Blood will be substituted with PEs in the hamster window chamber model which can be studied without complications of anesthesia and for long periods. An extreme hemodilution and a hemorrhagic shock model followed by continuous bleeding will be used to simulate realistic clinical conditions. Strategies for optimal follow up of plasma resuscitation and exchange with blood transfusion will be investigated.